The human spine is formed from twenty-six consecutive vertebrae. Each of these vertebrae is separated from any adjacent vertebra by an intervertebral disc that functions to absorb shock and prevent each vertebra from directly impacting upon another vertebra. At the center of each disc is a nucleus pulposus that contains proteoglycan. Around the nucleus pulposus is an outer ring called the annulus fibrosus. Degenerative disc disease refers to any of the common degenerative conditions of the lower spine involving degeneration of the disc. Disc degeneration is often associated with the symptom of pain and may lead to inflammation and neuropathic pain, for example, spinal stenosis, spondylolisthesis, and retrolisthesis.
Disc degeneration associated with the aging process is generally associated with the loss of proteoglycan from the nucleus pulposus of the spinal discs and a reduction of the disc's ability to absorb shock between vertebrae. Although some affected patients may not exhibit symptoms, many affected patients suffer from chronic back and/or leg pain. Pain associated with disc degeneration may become debilitating and may greatly reduce a patient's quality of life.
While non-operative treatments for disc degeneration exist, many patients, for example, those patients with severe symptoms, may not respond to non-operative treatment. Conventional operative treatment generally involves spondylosyndesis (spinal fusion), which is highly invasive and is associated with certain risks to the patient.
While the biological mechanisms of degenerative disc disease are not well known, it is known that proteoglycans, which are abundant in the disc's nucleus pulposus, decline in content with age, are believed to be an important factor in the pathogenesis of the disease. Degenerated and herniated discs are known to produce increased amounts of proteins such as nitric oxide (NO), cytokines, such as interleukin-1 (IL-1 and IL-1.beta.), interleukin-6 (IL-6) and TNF-alpha, prostaglandin E2 and matrix metalloproteases (MMP). These proteins play a regulatory role in the interactions between the biochemical agents produced by degenerated discs.
One drug class that is known to the medical profession is the alpha adrenergic receptor agonists. In general, the alpha-adrenergic receptors mediate excitatory and inhibitory functions: alpha-1 adrenergic receptors are typically excitatory post-synaptic receptors which generally mediate responses in the effector organ, while alpha-2 adrenergic receptors are located postsynaptically as well as presynaptically, where they inhibit release of neurotransmitters.
Examples of alpha adrenergic receptor agonists used clinically to treat different condition include clonidine, phenoxybenzamine and prazosin (for treatment of hypertension and opioid withdrawal), naphazoline (for nasal decongestion), UK-14,304 and p-aminoclonidine (for—glaucoma).
However, to date alpha adrenergic receptor agonists have not been widely appreciated as effective treatments for pain and/or inflammation resulting from degenerative disc disease and/or facet joint pain and inflammation. Thus, there is a need to develop alpha adrenergic receptor agonists to prevent, treat or reduce pain and/or inflammation resulting from degenerative disc disease and/or facet joint pain and inflammation.